Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy

靶向前列腺癌中的 Polo 样激酶 1 以增强治疗效果

基本信息

批准号：
10650837
负责人：
Zhiguo Li
金额：
$ 43.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650837
关键词：
Alleles Androgens Apoptosis Autophagocytosis Biometry Breeding Cancer Etiology Cancer Patient Cell Survival Cells Cellular biology Cessation of life Clinic Clinical Research Creativeness Data Disease Enterobacteria phage P1 Cre recombinase Fostering Genetically Engineered Mouse Goals Health Immune checkpoint inhibitor Immunocompetent Immunosuppression Immunotherapy Infiltration Investigation Lymphocyte Malignant Neoplasms Malignant neoplasm of prostate Measurement Mediating Membrane Mission Molecular Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Oncology Outcome Oxidative Stress PDL1 inhibitors PDL1 pathway PLK1 gene Pathology Patient-Focused Outcomes Patients Phosphorylation Phosphotransferases Play Prognosis Proliferating Prostate Cancer therapy Public Health Reactive Oxygen Species Refractory Regulation Research Residual state Role Signal Pathway Signal Transduction Survival Rate Testing Therapeutic Therapeutic Agents Therapeutic Effect Treatment Efficacy Tumor Escape Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Work advanced prostate cancer androgen deprivation therapy anti-PD-L1 therapy cancer cell castration resistant prostate cancer cell growth comparative efficacy design effective therapy immune cell infiltrate improved inhibitor innovation men mortality mouse model neoplastic cell novel novel strategies novel therapeutic intervention nuclear factor-erythroid 2 pharmacologic programmed cell death ligand 1 programs promoter prostate cancer cell prostate cancer progression receptor response synergism targeted treatment therapeutically effective tumor tumor growth tumor microenvironment tumor xenograft tumor-immune system interactions

项目摘要

Title: Targeting Polo-like kinase 1 in prostate cancer to enhance therapeutic efficacy Abstract Prostate cancer (PCa) is the second most common cause of cancer death in men in the US. Over the past several decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed into a poor prognosis stage of castration-resistant prostate cancer (CRPC), which eventually led to mortality. And the current therapeutic agents for CRPC patients only extend survival by around 2.5 - 5 months. Therefore, novel and effective therapeutic strategies for CRPC patients are urgently needed. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to identify the role of Plk1/p62/Nrf2 signaling pathway in CRPC, and to exploit the potentially therapeutic strategies that could be benefit the CRPC patients. The central hypothesis is that Nrf2 is activated by a noncanonical mechanism involving p62 phosphorylation by Plk1 in CRPC. Our hypothesis will be tested by pursuing Three Specific Aims: (1) to determine the novel role of Plk1 as regulator of cellular response to oxidative stress. (2) examine the role of Plk1/p62/Nrf2 axis in tumor growth in mouse models. And (3) whether inhibition of Plk1/p62/Nrf2 signaling pathway enhance the efficacy of CRPC therapy. The expected results will reveal a novel molecular mechanism to show how Plk1 contributes to PCa progress, and will open up new avenues for application of Plk1 inhibitors as a therapeutic option. The team, with expertise in Plk1 in mouse models, Plk1 in cancer cell biology, PCa pathology, GU oncology and biostatistics, will be able to finish the proposed research in a timely manner.

标题：在前列腺癌中靶向类似polo样激酶1以增强治疗功效抽象的前列腺癌（PCA）是美国男性癌症死亡的第二大最常见原因。过去几十年来，雄激素剥夺疗法一直是患者的主要治疗选择高级PCA;然而，大多数患者发展为耐Castration的预后不良阶段前列腺癌（CRPC），最终导致死亡率。以及当前CRPC的治疗剂患者仅将存活率延长约2.5至5个月。因此，新颖有效的治疗策略迫切需要CRPC患者。这项研究的长期目标是确定可毒的信号传导为CRPC患者提供更有效的治疗选择的途径。目的是确定角色 CRPC中PLK1/p62/NRF2信号通路的受益于CRPC患者。中心假设是NRF2被非规范机制激活 PLK1在CRPC中涉及p62磷酸化。我们的假设将通过追求三个具体目标来检验：（1）确定PLK1作为细胞对氧化应激反应的调节剂的新作用。（2）检查角色小鼠模型中肿瘤生长中PLK1/p62/nrf2轴的of。（3）抑制PLK1/p62/nrf2信号传导是否抑制途径增强了CRPC治疗的功效。预期的结果将揭示一种新型的分子机制为了展示PLK1如何促进PCA进度，并将为应用PLK1抑制剂的新途径开放作为治疗选择。该团队在鼠标模型中具有PLK1的专业知识，PLK1在癌细胞生物学中，PCA 病理学，GU肿瘤学和生物统计学将能够及时完成拟议的研究。